NOTE * E-mail: shaohw@cib.ac.cn; Fax: 0086-028-82890288 Received February 5, 2014; accepted March 20, 2014; published online April 4, 2014. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400070 or from the author. Chin. J. Chem. 2014, 32, 361—364 © 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 361 DOI: 10.1002/cjoc.201400070 An Efficient and Simple Method for Stereoselective Synthesis of N-Substituted Iminosugars from D-Xylose Derivative Jichao Zhang, a,b Wen Yuan, a,b Xiaofeng Ma, a,b Haibo Wang, a,b and Huawu Shao* ,a a Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China b University of Chinese Academy of Sciences, Beijing 100049, China A series of new N-substituted iminosugars were successfully synthesized through a general synthetic route from D-xylose derivative. This approach provided a convenient access to the synthesis of N-alkylated iminosugars as po- tential glucosidase inhibitors, which included a reaction of reductive amination. Various N-alkylated iminosugars were prepared in good yields with high stereoselectivity. Keywords iminosugars, stereoselective synthesis, N-alkylation, reductive amination, Michael addition Introduction Polyhydroxypiperidines, also named iminosugars (or azasugars) [1,2] are carbohydrate mimetics, where nitro- gen atom replaces the oxygen in the ring system tem- plate. The most attractive properties of iminosugars are their potential biological activities toward glycosidase [3] and glycosyl transferases inhibitors. [4] They also have great potential as drugs to treat various diseases such as diabetes, [5] Gaucher′s disease, [6] HIV infection [7] and other diseases. For example, iminosugar derivatives (Miglitol [8] and Miglustat [6,9] ) have been the listed medicines in the treatment of type 2 diabetes and Gaucher′s disease. Attracted by the interesting activity, a number of excellent works have been done to study the synthesis and biological activity associated with iminosugars. [10] Furthermore, many examples indicate that as enzyme inhibitors, the ability and selectivity of iminosugars are highly dependent on the 1-C-branch and the substituted group on nitrogen atom. [11] The ini- tial therapeutic application promoted the further explo- ration of N-substituted iminosugars. [9,12] Thus, it is very significant to establish a general approach to synthesize various substrates for their biological activity study. Previously, started from D-ribose, we have reported the synthesis of N-substituted iminosugars from 5-al- kylamine-1-C-(2'-oxoalkyl)-glycosides by subsequent base-mediated β-elimination and intramolecular Mi- chael addition. As our continued interests in the stereo- selective synthesis of substituted sugars, [13] herein, we report an efficient approach for the preparation of a se- ries of new N-substituted iminosugars through a general synthetic route starting from D-xylose derivate (Scheme 1), which are beneficial to the construction of imino- sugar library. Notably, this approach is particularly convenient for the synthesis of N-substituted 1-C- branched iminosugars. Scheme 1 Synthesis of N-substituted iminosugars starting from D-xylose derivative OBn OBn O N 3 O OBn NH 2 HO BnO O N H HO OBn OBn O N HO OBn OBn O R RCHO phenyl, o-Cl-phenyl, m-Cl-phenyl, p-OCH 3 -phenyl, p-NO 2 -phenyl, p-CH 3 -phenyl, furyl (β-elimination) Michael addition (1) Pd/C, H 2 , MeOH 1 2 3a - 3l 0 o C - r.t. (2) NaOMe/MeOH MeOH, NaBH(AcO) 3 R = C 2 H 5 , n-propyl, iso-propyl, C 6 H 13 , p-Cl-phenyl, Experimental The procedure for the preparation of the starting material 1 in Scheme 1 and all the final products listed in Scheme 2 are included in the supporting information. Synthesis of compound 2: To a solution of 1 (500 mg, 1.3 mmol) in methanol (8 mL) was added 10% Pd/C (250 mg) under hydrogen atmosphere. After the